Assessment of 12-week safety in subjects dosed with 40 and 60 mg of GSK2336805 when given in combination with pegylated interferon alpha-2a and ribavirin as measured by the nature and frequency of adverse events and absolute values.

Antiviral activity of 40 and 60 mg of GSK2336805 when given in combination with pegylated interferon alpha-2a and ribavirin. [ Time Frame: 12-week treatment period ] [ Designated as safety issue: No ]

Assessment of 12-week tolerability in subjects dosed with 40 and 60 mg of GSK2336805 when given in combination with pegylated interferon alpha-2a and ribavirin as measured by changes over time from predose values for hematology, clinical chemistry, urinalysis, vital sign measurements (blood pressure, heart rate), and ECG parameters.

Sustained virologic response rates between GSK2336805 and standard of care [ Time Frame: 24 weeks after start of treatment period ] [ Designated as safety issue: No ]

Compare sustained virologic response (SVR) rates among subjects who receive a total of 24 weeks of therapy (12 weeks of GSK2336805 and pegylated interferon alpha-2a and ribavirin followed by 12 weeks of pegylated interferon alpha-2a and ribavirin) versus those who receive the current standard of care (pegylated interferon alpha-2a, ribavirin and telaprevir based on label recommendations).

Evaluate the potential of hepatitis C virus to develop resistance against GSK2336805 by repeated sequencing of HCV strains. Analysis of the viral genotyping samples will be dependent on the subject's HCV viral load data. All study participants in a GSK2336805 treatment group will have genotypic analysis performed on the baseline sample. Samples from non-responders and subjects who rebound on GSK2336805 treatment will be subject to further genotypic analysis at nadir and at several time points after nadir.

Further characterize the antiviral activity and safety of 60 mg of GSK2336805 in subjects with chronic genotype 4 hepatitis C virus (HCV) infection. GSK2336805 (60 mg) will be given in combination with pegylated interferon alpha-2a and ribavirin for 12 weeks, followed by pegylated interferon alpha-2a and ribavirin alone for either 12 or 36 weeks (based on the achievement of extended rapid virologic response).

Describe exposure-response relationships of GSK2336805 for example the relationship between GSK2336805 dose or plasma exposure and measures of virologic response when given in combination with pegylated interferon alpha-2a and ribavirin.

Evaluate 12-week safety in subjects dosed with 40 and 60 mg of GSK2336805 when given in combination with pegylated interferon alpha-2a and ribavirin followed by either 12 or 36 weeks of combination therapy with pegylated interferon alpha-2a and ribavirin based on response guided treatment (RGT) as measured by the nature and frequency of adverse events and absolute values.

Evaluate 12-week tolerability in subjects dosed with 40 and 60 mg of GSK2336805 when given in combination with pegylated interferon alpha-2a and ribavirin followed by either 12 or 36 weeks of combination therapy with pegylated interferon alpha-2a and ribavirin based on response guided treatment (RGT) as measured by changes over time from predose values for hematology, clinical chemistry, urinalysis, vital sign measurements (blood pressure, heart rate), and ECG parameters.

An additional nonrandomized single-arm cohort of subjects with chronic genotype 4 HCV infection will be enrolled in parallel. A maximum of 15 genotype 4 subjects will receive GSK2336805 60 mg and PEG + RIBA. The purpose of this cohort is to further characterize the antiviral activity of GSK2336805 in subjects with chronic genotype 4 HCV infection. The schedule of assessments for the genotype 4 subjects will be the same as for the genotype 1 subjects. Recruitment of the genotype 4 subjects may be terminated when the target sample of genotype 1 subjects have been randomized.

Subjects in a GSK2336805 treatment arm who achieve extended rapid virologic response (eRVR) will receive a total of 24 weeks of therapy (12 weeks GSK2336805 in combination with PEG + RIBA followed by 12 weeks PEG + RIBA). Subjects who are HCV detectable at Week 4 and then undetectable at Week 12 will receive a total of 48 weeks of therapy (12 weeks GSK2336805 in combination with PEG + RIBA followed by 36 weeks PEG + RIBA). Subjects in the telaprevir treatment control arm will be managed according to the current product label for treatment-naïve subjects.

Subjects who complete treatment will undergo follow-up monitoring for 24 weeks after completion of therapy. At the end of the 24-week follow-up visit, subjects will have completed their participation in the study. The total duration of the study will be 48 weeks for subjects who achieve eRVR at Week 12 and up to 72 weeks for subjects who do not achieve eRVR at Week 12.

Eligibility

Ages Eligible for Study:

18 Years to 70 Years

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

Chronic HCV infection documented by at least 1 measurement of serum HCV RNA greater than or equal to 100,000 IU/mL measured during Screening by the COBAS High Pure/COBAS TaqMan HCV Test v2.0 and at least one of the following:

A positive anti-HCV antibody, HCV RNA, or HCV genotype test at least 6 months prior to Baseline (Day 1) together with positive HCV RNA and anti-HCV antibody tests at the time of Screening; or

A positive HCV RNA test and anti-HCV antibody test at the time of Screening together with either a liver biopsy consistent with chronic HCV infection (or a liver biopsy performed before enrollment with evidence of chronic hepatitis C disease, such as the presence of fibrosis).

Naïve to all HCV antiviral treatment(s), including, but not limited to, immunomodulatory and nucleoside/nucleotide treatments for chronic HCV infection.

Agree to interleukin 28B (IL28B) genotyping.

A subject, who, in the opinion of the investigator, is an appropriate candidate for pegylated interferon alpha-2a (PEG)/ribavirin (RIBA)/protease inhibitor combination therapy for genotype 1 subjects and PEG/RIBA combination therapy for genotype 4 subjects.

Body mass index >18 kg/m2 but not exceeding 36 kg/m2.

A liver biopsy obtained within 3 years (36 calendar months) prior to the Day 1 visit, with a fibrosis classification of noncirrhotic as judged by a local pathologist (defined as Knodell less than or equal to 3, Metavir less than or equal to 2, Ishak less than or equal to 4, or Batts and Ludwig less than or equal to 2). Both incomplete and transition to cirrhosis (e.g., Metavir score 3) are considered as cirrhosis. If no recent (<36 months) liver biopsy is available, a study-qualifying biopsy must be performed prior to Baseline (Day 1).

All fertile males and females must use 2 forms of effective contraception between them during treatment and during the 24 weeks after treatment ends.

Females, is eligible to enter and participate in the study if of non-childbearing potential (i.e., physiologically incapable of becoming pregnant) and includes any female who has had a hysterectomy or has had a bilateral oophorectomy (ovariectomy) or has had a bilateral tubal ligation or is postmenopausal (demonstrate total cessation of menses for greater than 1 year).

Females, is eligible to enter and participate in the study if of childbearing potential and has a negative urine or serum pregnancy test at Screening and within the 24-hour period prior to the first dose of study medication and completely abstains from intercourse for 2 weeks before exposure to the study medication, throughout the clinical study, and for 24 weeks after completion or premature discontinuation from this study or uses 2 of the following acceptable methods of contraception throughout the clinical study and for 24 weeks after completion or premature discontinuation from this study:

Any intrauterine device with a documented failure rate of <1% per year

Total bilirubin greater than or equal to 2.0 × ULN (except subjects with Gilbert's syndrome)

Albumin less than or equal to 3.0 g/dL

Platelet count less than or equal to 90,000/mm3

History of major organ transplantation with an existing functional graft

Thyroid dysfunction not adequately controlled

History of suicide attempt or hospitalization for depression in the past 5 years

History of any current (within 6 months) severe or poorly controlled psychiatric disorder

Subjects who have had a severe or poorly controlled psychiatric disorder more than 6 months ago but less than 5 years ago are eligible for study participation but must be assessed and followed (if recommended) by a mental health professional.

History or current evidence of immunologic disorder; cardiac or pulmonary disease; seizure disorder; or cancer or history of malignancy that in the opinion of the investigator makes the subject unsuitable for the study.

Treated with herbal or natural remedies with antiviral activity within 30 days of the baseline visit or has a history of having received any systemic antineoplastic or immunomodulatory treatment (including mycophenolate mofetil, thymosin alpha, supraphysiologic doses of steroids >10 mg/day and radiation) within 6 months of the baseline visit or expects that such treatment will be needed at any time during the study.

Participated in a clinical study with an investigational drug, biologic, or device within 3 months prior to the first dose administration.

History of a known allergy to antiviral medications, including telaprevir, pegylated interferon alpha-2a (PEG), ribavirin (RIBA), or any excipient in the investigational product or history of drug or other allergy that, in the opinion of the investigator, contradicts participation.

Requires prohibited medications

Contacts and Locations

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To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01648140